We have demonstrated that administration of DTP vaccine to mice causes alterations in hepatic drug metabolism in a dose and time deopendent manner. The mechanism for the observed changes is unknown, as are the components responsible for the alterations. Endotoxin is a common component of many bacterial vaccines and causes a variety of effects in vivo. In order to understand the role of LPS in vaccine-induced hepatotoxicity, endotoxin sensitive and endotoxin resistant mice have been treated with vaccines and endotoxin. There is a marked difference in hexobarbital-induced sleep times between LPS-sensitive and LPS-resistant mice treated with 50 mg of B.pertussis LPS. In contrast, DTP vaccine pretreatment causes the same response in both strains of mice. When the endotoxin inhibitor polymyxin B is mixed with vaccine or endotoxin prior to injection, the increased sleep time due to endotoxin administration is eliminated while that of the DTP vaccine is only reduced about 20%. RNA from the livers of mice treated with endotoxin and DTP vaccine have been isolated. We are using cDNA probes specific for different cytochrome P-450 isozymes to compare the pattern of inhibition in the two strains of mice following endotoxin and vaccine administration. Serum cytokine levels (IL6 and TNF) are elevated in a number of disease states or following injury or trauma. We have found that IL6 is elevated 2-4 hours after a single dose of vaccine or endotoxin. There is appoximately a 10-fold difference in IL6 levels between endotoxin-sensitive and resistant mice following endotoxin administration. In contrast, DTP vaccine does not increase IL6 levels as much, and the diffference between strains of mice is much less pronounced. Further, administration of endotoxin mixed with polymyxin reduced the elevation in IL6 about 100 fold, while only decreasing the DTP vaccine response 3 fold. These results suggest that endotoxin is not responsible for all of the effects of DTP vaccine. Studies are continuing to identify other factors which may be involved.